Doxorubicin is a known anthracycline antibiotic described for example in U.S. Pat. No. 3,590,028. Doxorubicin, and the closely related compound daunomycin, are antineoplastic agents of established clinical utility. Doxorubicin hydrochloride, available from Adria Laboratories, Inc., under the trademark Adriamycin.sup.(R), has been approved by the Food and Drug Administration for use in clinical research, and is one of the most powerful anticancer drugs available against numerous forms of cancer.
At present, doxorubicin is produced commercially from a soil fungus by a fermentation process. A suitable fermentation technique for preparing doxorubicin is described in U.S. Pat. No. 3,590,028. Such techniques are inherently expensive and limit the types of molecules that can be produced. Because of the inherent disadvantages of presently available commercial techniques for producing doxorubicin and related compounds, substantial effort has been devoted to developing processes for producing such compounds by chemical synthesis.
Techniques for the synthesis of anthracycline antibiotics such as doxorubicin are known. See, e.g., Wong et al., Canadian Journal of Chemistry, Vol. 51, page 466 (1973); Acton et al., Journal of Medicinal Chemistry, Vol. 17, No. 6, page 659 (1974); Kende et al., Journal of the American Chemical Society, Vol. 97, No. 15, page 4425 (1975) and Vol. 98, No. 7, page 1967 (1976); Sih et al., Tetrahedron Letters, page 3385 (1976); Swenton et al., Tetrahedron Letters, pages 2383 (1977); and Kelly et al., Journal of the American Chemical Society, Vol. 99, page 5513 (1977). None of the known techniques for the total synthesis of anthracycline antibiotics such as doxorubicin have yet been proven to be commercially successful. Because of the demand for, and scarcity of, these compounds, a suitable synthesis technique is highly desired.
The present invention provides a practical technique for synthesizing doxorubicin and related compounds, from readily available and inexpensive starting materials. Specifically, and in accordance with the present invention, doxorubicin and similar compounds may be synthesized from butadiene and p-benzoquinone. In addition, the present invention provides valuable intermediate compounds that are useful in synthesizing doxorubicin and related compounds.